Epigenetic regulatory mechanisms in vertebrate eye development and disease

Abstract

Eukaryotic DNA is organized as a nucleoprotein polymer termed chromatin with nucleosomes serving as its repetitive architectural units. Cellular differentiation is a dynamic process driven by activation and repression of specific sets of genes, partitioning the genome into transcriptionally active and inactive chromatin domains. Chromatin architecture at individual genes/loci may remain stable through cell divisions, from a single mother cell to its progeny during mitosis, and represents an example of epigenetic phenomena. Epigenetics refers to heritable changes caused by mechanisms distinct from the primary DNA sequence. Recent studies have shown a number of links between chromatin structure, gene expression, extracellular signaling, and cellular differentiation during eye development. This review summarizes recent advances in this field, and the relationship between sequence-specific DNA-binding transcription factors and their roles in recruitment of chromatin remodeling enzymes. In addition, lens and retinal differentiation is accompanied by specific changes in the nucleolar organization, expression of non-coding RNAs, and DNA methylation. Epigenetic regulatory mechanisms in ocular tissues represent exciting areas of research that have opened new avenues for understanding normal eye development, inherited eye diseases and eye diseases related to aging and the environment.

Figure 1

A schematic diagram of mammalian eye development (a–c) and structure of the mature retina (d). See text for details, periocular mesenchyme (POM). Ganglion cells mark the ganglion cell layer (GCL) and their axons form the optic nerve, targeting synaptic connections in the optic chiasm of the brain. The inner plexiform layer (IPL) contains several substrata where ganglion cells synapse with bipolar cells of the inner nuclear layer (INL). The INL also contains amacrine and horizontal cells, which form horizontal connections. Bipolar cells are interneurons that also synapse with rod- and cone-photoreceptors of the outer nuclear layer (ONL), forming connections in the outer plexiform layer (OPL). Photoreceptor cell nuclei (mostly rods seen here) comprise the ONL, whereas their inner segments (IS) and sensory outer segments (OS) are situated adjacent to the retinal pigment epithelium (RPE). Muller glial cell processes span the neural retina from the GCL to the ONL/OS boundary. Their nuclei tend to position in the INL.

Figure 2

Chromatin-regulatory enzymes and their modular organization. Representative members of histone acetyltransferases (EP300/p300, PCAF and TAF1), deacetylases (HDAC1), methyltransferases (MLL1), demethylases (KDM1, KDM2A, and KDM5a), and ATP-helicases (SMARCA4 and SMARCA5) are shown with their catalytical and structural domains. Additional information on recognition of core histone modifications by bromodomain and PHD finger are given in Table 3 and in recent reviews (Klose et al., 2006; Ruthenburg et al., 2007; Taverna et al., 2007). AOD, aminooxidase domain; ARID/BRIGHT, AT-rich interactive domain; Bromo, bromodomain; deacetylase, deacetylase type I; HAT, histone acetyltransferase; helicase, DEAD/H-box helicase domain (ATPase); JmjC, Jumonji C demethylase catalytical core; JmjN, Jumonji N-terminal domain associated with the JmjC; kinase, protein serine/threonine kinase domain; PHD, PHD zinc-finger; SANT, nucleosome interacting domain; SET, protein methylase domain; SWIRM, α-helical protein–protein interaction domain; Zn-finger, various Zn-finger domains.

Figure 3

A general model of gene activation of tissue-specific genes during embryonic eye development. A condensed chromatin domain, shown as 30 nm fiber, is marked by the presence of compacted nucleosomes marked by repressive PTMs (red octagons), and the presence of chromatin remodeling enzymes such as HDACs. The process of gene activation is initiated through binding of a TF (yellow) that can recognize its target sites in ‘closed’ chromatin conformation. Recruitment of distinct chromatin remodeling complexes/enzymes (for example, CR1 and CR2) through TF results in the generation of a novel set of histone PTMs, enriched for activating modifications (green octagons-methylations, blue flags-acetylations) and transition to the 11 nm chromatin conformation. Within this ‘open’ chromatin structure, TF1 (purple) and TF2 (orange), can locate their corresponding binding sites, and recruit additional nucleosome remodeling activities by reading the histone code that promotes transcription (Tx). It is possible that binding of the original TF (yellow) is no longer required at the binding site(s). See text for additional details.